Oral Exposure to Titanium Dioxide E171 and Zinc Oxide Nanoparticles Induces Multi-Organ Damage in Rats: Role of Ceramide.

Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are common food additives for human consumption. We examined multi-organ toxicity of both compounds on Wistar rats orally exposed for 90 days. Rats were divided into three groups: (1) control (saline solution), (2) E171-exposed, and (3) ZnO NPs-exposed. Histological examination was performed with hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Ceramide (Cer), 3-nitrotyrosine (NT), and lysosome-associated membrane protein 2 (LAMP-2) were detected by immunofluorescence. Relevant histological changes were observed: disorganization, inflammatory cell infiltration, and mitochondrial damage. Increased levels of Cer, NT, and LAMP-2 were observed in the liver, kidney, and brain of E171- and ZnO NPs-exposed rats, and in rat hearts exposed to ZnO NPs. E171 up-regulated Cer and NT levels in the aorta and heart, while ZnO NPs up-regulated them in the aorta. Both NPs increased LAMP-2 expression in the intestine. In conclusion, chronic oral exposure to metallic NPs causes multi-organ injury, reflecting how these food additives pose a threat to human health. Our results suggest how complex interplay between ROS, Cer, LAMP-2, and NT may modulate organ function during NP damage.

Association of Childhood Blood Pressure with Left Atrial Size and Function: Study of High Blood Pressure in Pediatrics-Adult Hypertension in Youth (SHIP AHOY).

OBJECTIVE(S): To evaluate the cross-sectional association of cardiovascular disease risk factors with left atrial (LA) size and function among healthy youth, aged 11-18 years, with a wide range of blood pressures (BPs). STUDY DESIGN: Echocardiographic images of youth enrolled in the Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth study were analyzed for LA measurements. The association of casual BP, ambulatory BP, and other cardiovascular disease risk factors with LA size and function were determined using descriptive statistics and multivariable regression. Regression models adjusting for age, sex, race, and body mass index z score determined the independent association between ambulatory systolic BP indices (mean systolic BP/50th %ile systolic BP) and BP phenotypes with LA outcomes while exploratory analyses investigated for additional predictors of LA outcomes. RESULTS: The study population consisted of 347 youth: median age 15.7 years, 60% male and 40% non-White. Greater-risk casual systolic BP groups had worse cardiometabolic profiles but no differences in LA size and function. Each 0.1 increase in ambulatory systolic BP day or night index was associated with a 9.9 mL/m2 increase in LA volume/body surface area (LAV/BSA; 95th% CI 2.8-17.0, P = .006) and a 6.8 mL/m2 increase in LAV/BSA (95th% CI 0.8-12.8, P = .03), respectively. Ambulatory hypertension was associated with greater odds of abnormal LAV/BSA, defined as >75th %ile (2014 ambulatory BP monitoring criteria: OR 3.2 [95th% CI 1.4-7.2; P = .002]; 2022 ambulatory BP monitoring criteria: OR 2.1 [95th% CI 1.0-4.1; P = .008]). CONCLUSIONS: Increasing ambulatory systolic BP and ambulatory hypertension are independently associated with LAV/BSA.

Protein kinase C-delta inhibition is organ-protective, enhances pathogen clearance, and improves survival in sepsis.

Sepsis is a leading cause of morbidity and mortality in intensive care units. Previously, we identified Protein Kinase C-delta (PKCδ) as an important regulator of the inflammatory response in sepsis. An important issue in development of anti-inflammatory therapeutics is the risk of immunosuppression and inability to effectively clear pathogens. In this study, we investigated whether PKCδ inhibition prevented organ dysfunction and improved survival without compromising pathogen clearance. Sprague Dawley rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Post-surgery, PBS or a PKCδ inhibitor (200µg/kg) was administered intra-tracheally (IT). At 24 hours post-CLP, there was evidence of lung and kidney dysfunction. PKCδ inhibition decreased leukocyte influx in these organs, decreased endothelial permeability, improved gas exchange, and reduced blood urea nitrogen/creatinine ratios indicating organ protection. PKCδ inhibition significantly decreased bacterial levels in the peritoneal cavity, spleen and blood but did not exhibit direct bactericidal properties. Peritoneal chemokine levels, neutrophil numbers, or macrophage phenotypes were not altered by PKCδ inhibition. Peritoneal macrophages isolated from PKCδ inhibitor-treated septic rats demonstrated increased bacterial phagocytosis. Importantly, PKCδ inhibition increased survival. Thus, PKCδ inhibition improved survival and improved survival was associated with increased phagocytic activity, enhanced pathogen clearance, and decreased organ injury.

Wharton's jelly-derived mesenchymal stem cells attenuate sepsis-induced organ injury partially via cholinergic anti-inflammatory pathway activation.

Sepsis induces organ dysfunction due to overexpression of the inflammatory host response, resulting in cardiopulmonary and autonomic dysfunction, thus increasing the associated morbidity and mortality. Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) express genes and secrete factors with anti-inflammatory properties, neurological and immunological protection, as well as improve survival in experimental sepsis. The cholinergic anti-inflammatory pathway (CAP) is mediated by α7-nicotinic acetylcholine receptors (α7nAChRs), which play an important role in the control of systemic inflammation. We hypothesized that WJ-MSCs attenuate sepsis-induced organ injury in the presence of an activated CAP pathway. To confirm our hypothesis, we evaluated the effects of WJ-MSCs as a treatment for cardiopulmonary injury and on neuroimmunomodulation. Male Wistar rats were randomly divided into four groups: control (sham-operated); cecal ligation and puncture (CLP) alone; CLP+WJ-MSCs (1 × 106 cells, at 6 h post-CLP); and CLP+methyllycaconitine (MLA)+WJ-MSCs (5 mg/kg body wt, at 5.5 h post-CLP, and 1 × 106 cells, at 6 h post-CLP, respectively). All experiments, including the assessment of echocardiographic parameters and heart rate variability, were performed 24 h after CLP. WJ-MSC treatment attenuated diastolic dysfunction and restored baroreflex sensitivity. WJ-MSCs also increased cardiac sympathetic and cardiovagal activity. WJ-MSCs reduced leukocyte infiltration and proinflammatory cytokines, effects that were abolished by administration of a selective α7nAChR antagonist (MLA). In addition, WJ-MSC treatment also diminished apoptosis in the lungs and spleen. In cardiac and splenic tissue, WJ-MSCs downregulated α7nAChR expression, as well as reduced the phospho-STAT3-to-total STAT3 ratio in the spleen. WJ-MSCs appear to protect against sepsis-induced organ injury by reducing systemic inflammation, at least in part, via a mechanism that is dependent on an activated CAP.

Dimethyl Fumarate Modulates Oxidative Stress and Inflammation in Organs After Sepsis in Rats.

Sepsis is defined as life-threatening organ dysfunction induced by a disrupted host response to infecting pathogens. Evidences suggest that oxidative stress is intrinsically related to sepsis progression. Dimethyl fumarate (DMF) is a novel oral therapeutic agent with anti-oxidant properties which exerts protective effects through activation of nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2). Thus, the aim of this study is to evaluate the effect of DMF in different organs of rats submitted to an animal model of sepsis. Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) procedure and sham-operated rats was considered control group. The experimental groups were divided into sham + vehicle, sham + DMF, sham + NAC, CLP + vehicle, CLP + DMF, and CLP + NAC. Rats were treated by oral gavage with DMF immediately after and 12 h after surgery, or NAC (s.c.) at 3, 6, and 12 h after surgery. Twenty-four hours after sepsis induction, neutrophil infiltration, nitrite/nitrate concentrations, oxidative damage to lipids and proteins, superoxide dismutase (SOD), and catalase (CAT) activities were evaluated in the heart, liver, lung, and kidney. Septic animals presented increased neutrophil infiltration, NO metabolism, oxidative damage to lipids and proteins, and decreases of SOD and CAT activities, mainly in the heart, liver, and lung, while DMF-treated animals showed significant reduction in neutrophil infiltration, NO metabolism, and oxidative damage followed by increased SOD and CAT activities. DMF is effective in preventing oxidative stress and inflammation in rats 24 h after sepsis induction.

Effects of Chronic Carvedilol administration on blood Pressure Variability and target Organ injury in rats with sinoaortic Denervation / Efectos de la administración crónica de carvedilol sobre la variabilidad de la presión arterial y el daño de órgano blanco en ratas con desnervación sinoaórtica

background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both in hyperten-sive and normotensive subjects, so its reduction should be considered as a new therapeutic goal. Objective: The aim of this study was to evaluate the effect of long-term oral carvedilol treatment on blood pressure, blood pressure variability and target organ injury in the left ventricle and thoracic aorta in a model of blood pressure liability. Methods: Twelve male Wistar rats submitted to sinoaortic denervation were treated during 8 weeks with a single dose of carvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variability measure-ments were performed. Left ventricular and thoracic aortic weights were determined and histological samples were prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor β (TGF-β) were quantified in the left ventricle and thoracic aorta. results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the control group (126±5 vs. 142±11 mmHg, p<0.05; SD: 2.9±0.5 vs. 6.0±0.5 mmHg; p<0.05). A lower amount of connective tissue was found in carvedilol-treated animals. The expression of TGF-β decreased in both organs after carvedilol treatment. Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability in sinoaortic-denervated rats, decreasing the degree of left ventricular fibrosis.

introducción: El incremento en la variabilidad de la presión arterial resulta un nuevo factor de riesgo para el desarrollo de daño de órgano blanco en individuos tanto hipertensos como normotensos, por lo que se postula que su reducción debe considerarse una posible nueva meta terapéutica. Objetivos: Evaluar el efecto del tratamiento a largo plazo con carvedilol sobre la presión arterial, su variabilidad y el daño de órgano blanco en el ventrículo izquierdo y la aorta torácica en el modelo de la labilidad de presión. Material y métodos: Se incluyeron 12 ratas Wistar macho sometidas a desnervación sinoaórtica, las cuales fueron tratadas durante 8 semanas con una única administración diaria de carvedilol 30 mg/kg o vehículo. Finalizado el tratamiento se realizó la medición de la presión arterial y de la variabilidad a corto plazo y la evaluación ecocardiográfica. Se determinó el peso del ventrículo y de la aorta torácica y se realizaron preparados histológicos sobre ambos tejidos. Se cuantificó la expresión de metaloproteinasa 2 (MMP-2) y factor de crecimiento transformante β (TGF-β) en el ventrículo izquierdo y la aorta torácica. resultados: El carvedilol redujo la presión arterial sistólica y su variabilidad en las ratas con desnervación sinoaórtica en comparación con el grupo control (126 ± 5 vs. 142 ± 11 mm Hg, p < 0,05; DE: 2,9 ± 0,5 vs. 6,0 ± 0,5 mm Hg; p < 0,05). Se evidenció menor cantidad de tejido conectivo en los animales tratados con carvedilol. La expresión de TGF-β se encuentra disminuida en ambos órganos luego del tratamiento con carvedilol. Conclusiones: El tratamiento crónico con carvedilol reduce significativamente la presión arterial y su variabilidad a corto plazo en ratas con desnervación sinoaórtica, disminuyendo el grado de fibrosis del ventrículo izquierdo.